Previous studies by the applicant have emphasized the role and nature of heme oxygenase in the degradation of heme and hemoproteins. An important finding in these studies was that the activity of heme oxygenase is markedly influenced by a wide variety of transition and toxic heavy metals. Furthermore, it also was shown that the regulatory effect of metal ions on heme biosynthesis is exerted mainly through initial inhibitory effect on the synthesis of delta-aminolevulinate synthetase, the first and rate-limiting enzyme of the heme biosynthetic pathway. It also has been observed that the administration of cobalt and nickel results in the depletion of cellular glutathione levels; it is well known that glutathione plays a central role in the detoxication of electrophilic metabolites of xenobiotics which are thought to function in the initiation of neoplastic transformation and in the production of cellular necrosis. Recently, we have shown that the observed depressed rate of activity of delta-aminolevulinate synthetase in the newborn is attributed to metal ions. Finally, this depressed activity can be reversed and restored to adult levels by the administration of chelating agents. The objectives of the proposed research are designed to expand our knowledge and understanding of metal ion toxcity and biological function. Specific points to be investigated include: (1) The role of metal ions in the depressed capacity of newborn to metabolize drugs and to explore means by which neonatal jaundice can be checked by inhibiting heme oxygenase. (2) To further characterize the enzymes involved in heme degradation and to investigate the role of metal ions on the activity of biliverdin reductase. (3) To study the effect of repeated exposure to metal ions on the response of the hepatic microsomal mixed function oxidase activity and heme metabolism pathway to the effect of a second exposure to metals and selected xenobiotics. In addition, the effect of exposure to important environmental contaminants namely toxic heavy metals on hepatic glutathione levels also will be investigated. (4) To elucidate the mechanism by which cytochrome P-450 is degraded in response to metal ion exposure and the role of ligandin in heme metabolism.